PROJECT SUMMARY The Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study (http://a4study.org/) is a ground-breaking study designed prevent cognitive decline among cognitively normal older adults who are amyloid positive. If successful, the A4 trial will demonstrate, for the first time, that it is possible to delay this devastating disease by initiating treatments prior to clinical manifestation. Such success would engender an effort to make treatments available globally. However, the only currently available means for screening older adults into potential trials (or regularity approved therapy) for amyloid-removing medications are amyloid PET scans or lumbar punctures (LPs), neither of which are viable options for large-scale screening. Here we propose to meet the objectives of PAR-15-359 by leveraging existing biorepository samples from the A4 trial. The long-term goal of this work is the establishment of a multi-tier neurodiagnostic approach for screening eligible older adults into clinical trials (and clinical intervention) of anti-amyloid agents to slow and/or prevent AD progression. The PIs are global leaders in blood-based biomarkers of AD. This project will leverage a substantial existing infrastructure to address the following Specific Aims: Aim 1: Validate our AD blood screen as the first step in screening cognitively normal older adults into prevention trials using anti-amyloid agents. Aim 2: Determine the accuracy of neuronally derived exosomes (NDEs) for screening cognitively normal older adults into prevention trials using anti-amyloid agents. Aim 3: Demonstrate the cost-benefit of a multi-tier screening process for enrollment into prevention studies of AD. The significance of the current proposal is the completion of the first-ever study of a blood-based Alzheimer's screening test as the first-step in a multi-tier screening process for prevention trials. The availability of such a process would increase access to both clinical trials and medications once FDA approved and provide a previously utilized strategy for reimbursement approval from other diseases.